Date of Award

4-22-2024

Embargo Period

5-7-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Azizul Haque

Second Advisor

Narenda Banik

Third Advisor

Lalima Madan

Fourth Advisor

Stephen Tomlinson

Fifth Advisor

Nathan Rowland

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease resulting in difficulty with motor coordination, balance, and speaking. Although the cause of PD remains unknown, oxidative damage, environmental toxins, genetic factors and accelerated aging have been implicated as potential causes for the disease. In addition, there is an aggregation of alpha-synuclein ( -syn), known as Lewy bodies, that activate an immune response involving microgliosis, inflammatory cytokines, and T-cell infiltration. These inflammatory immune responses may result in the activation of the Rho/Rho-associated coiled-coil containing protein kinase (Rho- ROCK) pathway, causing subsequent dopaminergic neuronal death in the substantia nigra (SN). Post-translational modification, truncation of -syn by an activated neutral cysteine protease, calpain, could promote the aggregation of -syn in the SN. Our laboratory has shown activation of calpain in the nigrostriatal pathway in animal models of PD, which promotes inflammatory pathways leading to neuroinflammation and neurodegeneration. In PD patients, increased expression of calpain is also detected in the brain and spinal cord, and that might cause aggregation of -syn and activation of inflammatory pathways. The activation of RhoA-/ROCK pathway by angiotensin II may also regulate actin cytoskeleton, further activating microglia and inflammatory cytokines/chemokines causing inflammation and neuronal death. Thus, blocking calpain activation may attenuate neuroinflammation which may further block activation of RhoA-ROCK pathway and neurodegeneration in PD.

Rights

Copyright is held by the author. All rights reserved.

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